rs9986447

Variant names:

• chr6-42975041-A-G
• rs9986447
• NM_000287.4:c.883-3T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000287.4(PEX6):​c.883-3T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.421 in 1,609,494 control chromosomes in the GnomAD database, including 148,312 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10783 hom., cov: 31)
  • Exomes 𝑓: 0.43 (137529 hom.)
• Consequence: PEX6 NM_000287.4 splice_region, intron
• Scores: Splicing: ADA: 0.0002058
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.428
• Publications: 35 publications found

Genes affected

PEX6 (HGNC:8859): (peroxisomal biogenesis factor 6) This gene encodes a member of the AAA (ATPases associated with diverse cellular activities) family of ATPases. This member is a predominantly cytoplasmic protein, which plays a direct role in peroxisomal protein import and is required for PTS1 (peroxisomal targeting signal 1, a C-terminal tripeptide of the sequence ser-lys-leu) receptor activity. Mutations in this gene cause peroxisome biogenesis disorders of complementation group 4 and complementation group 6. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

PEX6 Gene-Disease associations (from GenCC):

• peroxisome biogenesis disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• peroxisome biogenesis disorder 4A (Zellweger)

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health
• peroxisome biogenesis disorder 4B

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Heimler syndrome 2

  Inheritance: AR Classification: MODERATE Submitted by: G2P
• autosomal recessive cerebellar ataxia-blindness-deafness syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Zellweger spectrum disorders

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 6-42975041-A-G is Benign according to our data. Variant chr6-42975041-A-G is described in ClinVar as Benign. ClinVar VariationId is 92791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.449 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX6	NM_000287.4	c.883-3T>C		splice_region_variant, intron_variant	Intron 1 of 16	ENST00000304611.13	NP_000278.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX6	ENST00000304611.13	c.883-3T>C		splice_region_variant, intron_variant	Intron 1 of 16	1	NM_000287.4	ENSP00000303511.8
PEX6	ENST00000244546.4	c.883-3T>C		splice_region_variant, intron_variant	Intron 1 of 14	1		ENSP00000244546.4

Frequencies

GnomAD3 genomes AF: 0.362 AC: 54812 AN: 151618 Hom.: 10782 Cov.: 31

Gnomad AFR AF: 0.230

Gnomad AMI AF: 0.583

Gnomad AMR AF: 0.324

Gnomad ASJ AF: 0.408

Gnomad EAS AF: 0.104

Gnomad SAS AF: 0.403

Gnomad FIN AF: 0.405

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.453

Gnomad OTH AF: 0.383

GnomAD2 exomes AF: 0.373 AC: 93610 AN: 251010 AF XY: 0.387

Gnomad AFR exome AF: 0.228

Gnomad AMR exome AF: 0.252

Gnomad ASJ exome AF: 0.414

Gnomad EAS exome AF: 0.105

Gnomad FIN exome AF: 0.402

Gnomad NFE exome AF: 0.449

Gnomad OTH exome AF: 0.409

GnomAD4 exome AF: 0.427 AC: 622873 AN: 1457760 Hom.: 137529 Cov.: 34 AF XY: 0.430 AC XY: 311688 AN XY: 725384

African (AFR) AF: 0.224 AC: 7494 AN: 33402

American (AMR) AF: 0.264 AC: 11824 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.413 AC: 10777 AN: 26120

East Asian (EAS) AF: 0.125 AC: 4960 AN: 39692

South Asian (SAS) AF: 0.432 AC: 37212 AN: 86138

European-Finnish (FIN) AF: 0.394 AC: 21054 AN: 53408

Middle Eastern (MID) AF: 0.467 AC: 2187 AN: 4686

European-Non Finnish (NFE) AF: 0.453 AC: 502787 AN: 1109418

Other (OTH) AF: 0.408 AC: 24578 AN: 60184

GnomAD4 genome AF: 0.361 AC: 54841 AN: 151734 Hom.: 10783 Cov.: 31 AF XY: 0.358 AC XY: 26570 AN XY: 74154

African (AFR) AF: 0.230 AC: 9505 AN: 41256

American (AMR) AF: 0.324 AC: 4936 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.408 AC: 1415 AN: 3464

East Asian (EAS) AF: 0.105 AC: 543 AN: 5186

South Asian (SAS) AF: 0.404 AC: 1938 AN: 4802

European-Finnish (FIN) AF: 0.405 AC: 4268 AN: 10538

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.453 AC: 30788 AN: 67934

Other (OTH) AF: 0.381 AC: 803 AN: 2110

Alfa AF: 0.401 Hom.: 9172

Bravo AF: 0.346

Asia WGS AF: 0.250 AC: 870 AN: 3478

EpiCase AF: 0.457

EpiControl AF: 0.459

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Oct 10, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The PEX6 c.883-3T>C variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 45827/121356 control chromosomes (9493 homozygotes) at a frequency of 0.3776245, which greatly exceeds the estimated maximal expected allele frequency of a pathogenic PEX6 variant (0.0019365), indicating that this variant is a benign polymorphism. Multiple clinical labs have classified the variant as benign. Taken together, this variant is classified as benign. -

Aug 07, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 21, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:2

Dec 23, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Peroxisome biogenesis disorder 4A (Zellweger) Benign:2

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Peroxisome biogenesis disorder 4A (Zellweger);C3553937:Peroxisome biogenesis disorder 4B;C4225267:Heimler syndrome 2 Benign:1

Aug 11, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Zellweger spectrum disorders Benign:1

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Heimler syndrome 2 Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Peroxisome biogenesis disorder Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Peroxisome biogenesis disorder 4B Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	8.3
DANN	Benign	0.80
PhyloP100		0.43
Mutation Taster		=72/28	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00021
dbscSNV1_RF	Benign	0.016
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs9986447; hg19: chr6-42942779; COSMIC: COSV55103559;